Shortly after the neutron was discovered by Chadwick in 1932, its potential use in the treatment of human malignancies was realized. The concept of nuclei having a characteristic effective cross-sectional area, expressed as units of 10.sup.-24 cm.sup.2 known as barn units, was introduced with this early work. The effective nuclear cross section of boron for neutron capture was known to be exceptionally large while borons neighbors in the periodic table, nitrogen and carbon, exhibited nuclear cross sections which were comparatively quite small.
Taylor, Proc. Roy. Soc., A47: 873 (1935) described the capture of thermal neutrons by .sup.10 B nuclei followed by the production of .sup.4 He.sup.2+ (.alpha.-particles) and .sup.7 Li.sup.3+ with about 2 MeV of kinetic energy distributed between these two heavy ion products. It was also determined (Taylor, supra) that the translational range of the product ions was particularly short; about 7.6 .mu. in photographic gelatin and 1.1 cm in air. Consequently, the lithium ion and the .alpha.-particle products were short-range, energetic species capable of imparting immense local damage to organic materials through ionization processes.
The boron neutron capture (BNC) reaction obtained with thermal, 293 K (0.025 eV), neutrons may be represented as shown in Equation (1): ##STR1## The .sup.11 B nucleus is incapable of undergoing a BNC reaction while the effective nuclear cross section of .sup.10 B is 3837 barns.
Two other nuclides, .sup.1 H and .sup.14 N, are abundant in tissue and participate in important neutron capture side-reactions which occur during BNCT and thus contribute important doses of background radiation to the subject. These two neutron capture reactions play a role, not because of enhanced nuclear cross sections of the target nuclei, but due to their very high concentrations in tissue. As disclosed in H. Hatanaka, Boron-Neutron Capture Therapy for Tumors (H. Hatanaka, Ed.), Nishimura Co. Ltd., Nigata, Japan, p. 5 (1986), the neutron capture reactons of .sup.1 H and .sup.14 N are as shown in Equations (2a) and (2b), respectively: EQU .sup.1 H+.sup.1 n.sub.th .fwdarw.[.sup.2 H].fwdarw..sup.2 H+2.23 MeV.gamma.(2a) EQU .sup.14 N+.sup.1 n.sub.th .fwdarw.[.sup.14 N].fwdarw.0.63 MeVp.sup.+ +C.sup.14 ( 2b)
where * represents a transient, excited state. The passage of a neutron through hydrogen-rich media, such as tissue, results in the slowing and scattering of these neutrons by collisions with nuclear protons of the H-atoms. Occasionally, a slowly moving neutron will be captured by such a proton and produce a deuteron accompanied by characteristic gamma radiation which contributes to the total radiation dose. In another competing capture reaction, the nitrogen atoms available in tissue may capture a low-energy neutron and generate .sup.14 C and an 0.63 MeV (kinetic energy) proton. The kinetic energy imparted to the .sup.7 Li.sup.3+ and .sup.4 He.sup.2+ ions derived from the BNC reaction and that similarly associated with the proton and .gamma.-photons, produced as shown in (2a) and (2b), is transferred to the surrounding media. Since all of these energetic nuclear reaction products, with the exception of the .gamma.-photons, are heavy particles, this kinetic energy transfer is rapid and takes place along a very short path length. The rate of linear energy transfer, LET, of these particles is characteristically high and the immense energy of these reactions is therefore deposited in a very small volume. As an example, the .sup.7 Li.sup.3+ and .sup.4 He.sup.2+ ions generated in the BNC reaction generate ionization tracks about 0.01 mm long or the equivalent of approximately one cell diameter. Thus, the high LET characteristic of particles produced by nuclear reactions which occur within tissue are especially lethal to affected cells due to the high density of deposited energy.
Ideally, those cells which carry large numbers of .sup.10 B nuclei are subject to destruction by BNC while neighboring cells that are free of .sup.10 B are spared, save for the contribution of the background .sup.1 H(n,.gamma.).sup.2 H and .sup.14 N(n,p).sup.14 C reactions. In order for the delivery of .sup.10 B to tumor cells to achieve this desired effect in BNCT the selectivity of boron delivery to tumor versus normal tissue, which is subject to neutron irradiation, should be as great as possible. In addition, the actual concentration of .sup.10 B in tumor must be sufficiently high to offer a localized binary therapeutic effect well above the background radiation dose delivered by the .sup.1 H(n,.gamma.).sup.2 H and .sup.14 N(n,p).sup.14 C neutron capture processes shown above. The minimum generally accepted .sup.10 B concentration necessary for effective BNC has been commonly believed to be between 10 and 30 .mu.g .sup.10 B/g tumor depending upon the precise location of the .sup.10 B with respect to vital components of the tumor cell structure. As the position of the .sup.10 B nuclei is changed from the external cell wall to the cytoplasm to the nucleus of the cell, the required concentration of .sup.10 B for effective BNCT decreases, as expected. Thus, cell wall-bound .sup.10 B might require 30 ppm or greater concentrations while .sup.10 B localized within the nucleus of the tumor cell might only require a concentration of 10 ppm or less. An additional factor is the steady state concentration of thermal neutrons in the targeted volume of tissue since very low neutron intensities require proportionally longer irradiation times to produce the required number of BNC events for effective therapy.
In 1936 Locher (G. L. Locher, "Biological Effects and Therapeutic Possibilities of Neutrons," Am. J. Roentgenol. 36: 1-13 (1936)) proposed using the boron neutron capture reaction in the treatment of tumors. This approach was termed boron neutron capture therapy (BNCT) and a few years later Kruger and Zahl et al. (P. G. Kruger, "Some Biological Effects of Nuclear Disintegration Products on Neoplastic Tissue," Proc. Natl. Acad. Sci. 26: 181-192 (1940); P. A. Zahl et at., "Some in vivo Effects of Localized Nuclear Disintegration Products on a Transplantable Mouse Sarcoma," Proc. Natl. Acad. Sci. 26: 589-598 (1940)) experimentally verified this concept and demonstrated the biological effectiveness of the fission fragments produced by slow neutrons interacting with .sup.10 B. The first clinical trials for human malignancies were carded out in the 1950s using a reactor beam at the Brookhaven National Laboratories to treat malignant gliomas of the brain. In these initial trials boric acid derivatives were used as the .sup.10 B carrier agent (L. E. Farr et at., "Neutron Capture Therapy With Boron inthe Treatment of Glioblastoma Multiforme," Am. J. Roentgenol. 71: 279-291 (1954); J. T. Godwin et al., "Pathological Study of Eight Patients With Glioblastoma Multiforme Treated By Neutron Capture Therapy Using Boron 10," Cancer (Phila.) 8: 601-615 (1955)). Because of the attenuation of the thermal neutrons in tissue and problems with necrosis of the calvarium, subsequent trials in the 1960s at the Massachusetts Institute of Technology Research Reactor used craniotomies both to remove as much tumor as possible and to expose the tumor bed directly to the slow neutron beam. Unfortunately, these trials showed no therapeutic benefit from this form of treatment and moreover, showed considerable damage to the endothelial linings of the blood vessels (A. K. Asbury et al., "Neutopathologic Study of Fourteen Cases of Malignant Brain Tumors Treated by Boron-10 Slow Neutron Capture Therapy," J. Neuropathol. Exp. Neurol. 31: 278-303 (1972); G. L. Brownell et al., "A Reassessment of Neutron Capture Therapy in the Treatment of Cerebral Gliomas," Seventh National Cancer Conference Proceedings, Philadelphia: Lippincott, 827-837 (1973)). This was attributed both to the high concentration of .sup.10 B in the blood at the time of treatment and to the relatively poorly penetrating characteristics of the collimated reactor beams used for treatment. Subsequently, H. Hatanaka, "A Revised Boron Neutron Capture Therapy For Malignant Brain Tumors. II.," J. Neurol. 209: 81-94 (1975), and H. Hatanaka and K. Sano, "A Revised Boron Neutron Capture Therapy for Malignant Brain Tumors. II.," J. Neurol. 204: 309-332 (1973), reported Japanese clinical trials of BNCT using Na.sub.2 B.sub.12 H.sub.11 SH (i.e., BSH) as a carrier agent. Trials have continued to the present time and the data indicates several longterm "cures" of patients with documented glioblastoma multiforme (H. Hatanaka, Boron-Neutron Capture Therapy for Tumors (H. Hatanaka, Ed.), Nishimura Co. Ltd., Nigata, Japan, p. 5 (1986)). Trials have also been initiated in Japan for malignant melanoma using a boronated form of phenylalanine as the boron carrier (Y. Mishima et al., "First Human Clinical Trial of Melanoma Capture: Diagnosis and Therapy," Strahlenther. Onkol. 165: 251-254 (1989)).
Despite the conceptual appeal of this treatment, BNCT has yet to develop into a clinically useful therapy due to problems with boron delivery and difficulties in using thermal neutrons. A tumor-selective boron carder has yet to be fully developed. The clinical experiences using BNCT have noted significant skin and vascular tissue toxicity as a result of poor tumor specificity of the boron delivery agents. In addition, since the pathways of the .sup.10 B fission products are in the range of one cell diameter, traditional BNCT theoretically requires that every clonogenic tumor cell be labeled with .sup.10 B in order to achieve a tumor cure.
In parallel with this work, other investigators began to use high energy neutrons generated by a cyclotron as another form of external beam radiotherapy (R. S. Stone, "Neutron Therapy and Specific Ionization," Am. J. Roentgenol. 59: 771-785 (1940)). Like the situation with BNCT, the early clinical trials showed considerable toxicity and little efficacy and the field languished until the 1950s when mammalian cell culture techniques revealed critical differences between neutron and photon postirradiation cell survival curves. Clinical trials were resumed at Hammersmith Hospital in London, England in the 1960s and since that time over 15,000 patients have been treated with fast neutrons for various malignancies. This immense data base has enabled an accurate estimation of the tolerance of most clinically relevant normal tissues to fast neutron radiotherapy (G. E. Laramore, "Injury to the Central Nervous System After High LET Radiation," in Radiation Injury to the Nervous System (P. H. Gutin et at., Eds.), Raven Press, New York, N.Y., pp. 341-360 (1991); G. E. Laramore and M. Austin-Seymour, "Fast Neutron Radiotherapy in Relation to the Radiation Sensitivity of Human Organ Systems," in Relative Radiosensitivies of Human Organ Systems, III. Advances in Radiation Biology (K. I. Altman and J. Lett, Eds.), Academic Press, Orlando, Fla., 15: 153-193 (1992)). Based upon randomized clinical trials and single-institution experiences, fast neutrons appear to offer a therapeutic advantage compared to conventional, megavoltage photon irradiation for the following tumor systems: salivary gland tumors (T. W. Griffin et at., "Neutron vs. Photon Irradiation of Inoperable Salivary Gland Tumors: Results of an RTOG-MRC Cooperative Randomized Study," Int. J. Radiat. Oncol. Biol. Phys. 15: 1085-1090 (1988)), locally advanced prostate cancer (G. E. Laramore et al., "Fast Neutron Radiotherapy for Locally Advanced Prostate Cancer: Final Report of an RTOG Randomized Clinical Trial," Am. J. Clin. Oncol. (CCT) 16: 164-167 (1993); K. J. Russell et al., "Eight Years Experience With Neutron Radiotherapy in the Treatment of Stages C and D Prostate Cancer: Updated Results of the RTOG 7704 Randomized Clinical Trial," Prostate 11: 183-193 (1987)), and sarcomas of bone and soft tissue (G. E. Laramore et al., "Fast Neutron Radiotherapy For Sarcomas of Soft Tissue, Bone, and Cartilage," Am. J. Clin. Conol. (CCT) 12: 320-326 (1989)). In a randomized trial for patients with inoperable salivary gland tumors, initial tumor clearance rates at the primary site were 85% for neutron-treated patients compared to 33% for photon-treated patients (p=0.01), respective local-regional control rates at 2 years were 67% vs. 17% (p=0.005), and 2 year survivals were 62% vs. 25% (p=0.10). These results were consistent with historical data. Ten-year data continue to show a therapeutic advantage to fast neutrons for salivary gland tumors. In the case of locally advanced prostate cancer, a randomized, clinical trial compared a combination of neutrons and photons (i.e., mixed beam) with photons alone. At 10 years, local control rates were 63% for the mixed beam group compared to 52% for the photon group (p=0.05) and respective survival rates were 42% vs. 27% (p=0.05) (G. E. Laramore et al., "Fast Neutron Radiotherapy for Locally Advanced Prostate Cancer: Final Report of an RTOG Randomized Clinical Trial,"in J. Clin. Oncol. (CCT) 16: 164-167 (1993)). In the case of sarcomas there have been no randomized clinical trials but a historical comparison between fast neutrons and conventional photon irradiation for inoperable tumor shows respective local control rates of 53% vs. 38% for soft tissue sarcomas, 55% vs. 21% for osteogenic sarcomas, and 49% vs. 33% for chondrosarcomas (G. E. Laramore et al., Am. J. Clin. Oncol. (CCT) 12: 320-326, supra)). For other tumor systems such as squamous cell tumors of the head and neck, esophageal carcinomas, and high grade gliomas of the brain, fast neutron radiotherapy has exhibited no improvement over conventional photon irradiation.
It has been previously proposed to utilize the boron neutron capture reaction to enhance fast-neutron therapy of malignant tumors. See, for example, F. M. Waterman et al., "The Use of .sup.10 B to Enhance the Tumor Dose in Fast-Neutron Therapy," Phys. Med. Biol. 23(4): 592-602 (1978); W. Saurwein et al., "Neutron Capture Therapy Using a Fast Neutron Beam: Clinical Considerations and Physical Aspects," Strahlenther. Onkol. 165: 208-210 (1989); W. Ziegler et al., "Fast Neutrons From the Essen Cyclotron Can Be Used Successfully For Neutron Capture Experiments In Vitro," Strahlenther. Onkol. 165: 210-212 (1989); P. Wootton et al., "Boron Neutron Capture Enhancement of the Tumor Dose in Fast Neutron Therapy Beams," Proceedings of the Fourth Internat. Symposium on Neutron Capture Therapy For Cancer, Sydney, Australia, Dec. 4-7, 1990; W. Sauerwein et al., "Boron Neutron Capture Therapy (BNCT) Using Fast Neutrons: Effects in Two Human Tumor Cell Lines," Strahlenther. Onkol. 166: 26-29 (1990); G. E. Laramore et al., "Boron Neutron Capture Therapy: A Means of Increasing the Effectiveness of Fast Neutron Radiotherapy," Proceedings of the 9th ICRR, W. C. Dewey et al., Eds., Academic Press, San Diego, Calif. (1991), pp. 617-622; P. Wootton et al., "Boron Neutron Capture Enhancement of the Tumor Dose in Fast Neutron Therapy Beams," Progress in Neutron Capture Therapy for Cancer, B. J. Allen et al., Eds., Plenum Press, New York (1992), pp. 195-198; and G. E. Laramore et al., "Boron Neutron Capture Therapy: A Mechanism for Achieving a Concomitant Tumor Boost in Fast Neutron Radiotherapy," J. Radiation Oncology Biol. Phys. 28: 1135-1142 (1994). Despite the advances that have been made in fast neutron therapy, most of the reported studies of enhancement of fast neutron therapy with .sup.10 B BNCT have involved the treatment of cells in vitro, and the successful application of this technique in vivo remains highly problematical.